Nifedipine Prevents Changes in Nitric Oxide Synthase mRNA Levels Induced by Cyclosporine

Abstract

Abstract-Cyclosporine toxicity mainly affects kidney and liver function. We have previously shown that cyclosporine nephrotoxicity alters kidney nitric oxide synthase mRNA pattern of expression. To determine if nitric oxide synthase expression changes are mediated directly by cyclosporine or by secondary hemodynamic alterations induced by cyclosporine, we evaluated if these effects are tissue specific and if nifedipine-induced vasodilation prevents these alterations. Uninephrectomized Wistar rats treated for 7 days with olive oil, cyclosporine (30 mg/kg), nifedipine (3 mg/kg), and nifedipineϩcyclosporine were studied. In vehicle and cyclosporine groups, the gene expression of the neuronal, inducible, and endothelial nitric oxide synthases in cerebellum, heart, intestine, liver, renal cortex, and medulla was evaluated. The administration of cyclosporine was associated with nephrotoxicity and hepatotoxicity, increased endothelial nitric oxide synthase mRNA levels in renal cortex and liver, and a decrease in inducible nitric oxide synthase and neuronal nitric oxide synthase in renal medulla. The mRNA levels of the 3 nitric oxide synthase isoforms were not affected in any other tissue. Nifedipine did not alter nitric oxide synthase expression in the control group but prevented changes associated with cyclosporine. These results suggest that cyclosporine-induced changes in the pattern of expression of the nitric oxide synthases may be secondary to its hemodynamic effects. (Hypertension. 2000;36:642-647.)Key Words: nitric oxide Ⅲ liver Ⅲ hypertension Ⅲ cyclosporine C yclosporine (CsA) is an immunosuppressor drug. Despite its beneficial effects, however, long-term use is frequently associated with hypertension, nephrotoxicity, and hepatotoxicity.Nephrotoxicity is the most common complication associated with CsA therapy. 1 It is characterized by renal vasoconstriction that induces a decrease in renal plasma flow and glomerular filtration rate. This side effect is usually reversible when CsA dose is reduced. However, even with normal blood levels or during long-term dosage, CsA can produce chronic hypertension and can be the cause of irreversible impairment of renal function. 2 The mechanism by which CsA induces hypertension remains unknown.Hepatotoxicity is a less common side effect, which is characterized by cholestasis and metabolic disturbances. 3,4 In isolated perfused rat liver, CsA administration produced a dose-dependent reduction of bile flow, increased the release of cytosolic and mitochondrial enzymes, and decreased oxygen consumption. 3 High blood levels of CsA in human allograft recipients have been associated with an increase in ␥-glutamyl transpeptidase, a liver enzyme that correlates with hepatotoxicity. 5 In one study, hepatic abnormalities developed in up to 32% of patients with endogenous uveitis treated with CsA. 6 CsA toxicity has been attributed to an imbalance of vasoactive substance release. 1 Recent studies have shown that nitric oxide (NO) is increased during CsA administration by a mechanism th...

Vasodilator Agents Protect against Indinavir Nephrotoxicity

“…Sanchez-Lozada et al showed that NF prevented declines in renal function in CsA-treated rats, with no interference in the expression of NOS isoforms. This suggests that the changes in the NOS isoform pattern of expression induced by CsA appear to be, at least in part, mediated by the haemodynamic alterations induced by this drug [22]. Travis et al showed that the vasodilator responses elicited by systemic injections of NO donors were markedly attenuated by NF, suggesting that NO relaxes resistance arteries 'in vitro' by inhibition of Ca 2+ channels [23].…”

Treatment of Hypertension Because of Immunosuppressive Therapy After Solid Organ Transplantation—Pharmacological Approach

“…53,54 It has also been proven to reduce cyclosporine-induced hyperreactivity of vascular smooth muscle to catecholamines and to reverse its negative effect on NO synthase activity in the kidney core. 14,55 However, it should be remembered that nondihydropyridine CCB (ie, verapamil and diltiazem) increase CsA and TAC by inhibiting CYP3A4. 56 Other antihypertensive drugs have also been studied in renal transplant patients with good results.…”

The Glomerulus: Mechanisms of Injury*

“…After the administration of CsA, an increase in the expression of endothelial nitric oxide synthase (eNOS) was detected at both the RNA and the protein level in the renal cortex in rats (Bobadilla et al 1998 andSanchez-Lozada et al 2000). After the administration of CsA, an increase in the expression of endothelial nitric oxide synthase (eNOS) was detected at both the RNA and the protein level in the renal cortex in rats (Bobadilla et al 1998 andSanchez-Lozada et al 2000).…”